The inhibitory effects of mitragynine on P-glycoprotein in vitro
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Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.
KeywordsMitragyna speciosa Korth Kratom Mitragynine P-glycoprotein Bidirectional transport assay
The authors would like to acknowledge MyBrain15 program and USM fellowship for sponsoring NR.
Author contribution statement
TML, MIA, GK, and SFS conceived and designed research. NR and AA conducted experiments. HAW contributed analytical tools for in silico screening. TML and NR analyzed data. TML wrote the manuscript. All authors read and approved the manuscript.
This fundamental work was supported in parts by the Fundamental Research Grant Scheme (Ministry of Education Malaysia) and RUI (USM) grant awarded to TML.
Compliance with ethical standards
No animals or human were used in this study.
Conflict of interest
The authors declare that they have no conflict of interests.
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